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Metabolic reprogramming and cellular senescence greatly contribute to cancer relapse and recurrence. In aging and treated prostate, persistent accumulating senescence-associated secretory phenotype (SASP) of cancer cells often limits the overall survival of patients. Novel strategic therapy with monoacylglycerol lipase (MGLL) upregulation that counters the cellular and docetaxel induced SASP might overcome this clinical challenge in prostate cancer (PCa). With primary comparative expression and survival analysis screening of fatty acid (FA) metabolism signature genes in the TCGA PCa dataset and our single center cohort, MGLL was detected to be downregulated in malignancy prostate tissues and its low expression predicted worse progression-free and overall survival. Functionally, overexpression of MGLL mainly suppresses NF-κB-driven SASP (N-SASP) which mostly restricts the cancer cell paracrine and autocrine tumorigenic manners and the corresponding cellular senescence. Further investigating metabolites, we determined that MGLL constitutive expression prevents lipid accumulation, decreases metabolites preferably, and consequently downregulates ATP levels. Overexpressed MGLL inhibited IκBα phosphorylation, NF-κB p65 phosphorylation, and NF-κB nuclear translocation to deactivate NF-κB transcriptional activities, and be responsible for the repressed N-SASP, partially through reducing ATP levels. Preclinically, combinational treatment with MGLL overexpression and docetaxel chemotherapy dramatically delays tumor progression in mouse models. Taken together, our findings identify MGLL as a switch for lipase-related N-SASP suppression and provide a potential drug candidate for promoting docetaxel efficacy in PCa.
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OBJECTIVE: To develop and validate a nomogram for predicting recurrence-free survival (RFS) for clinical T1/2 (cT1/2) clear cell renal cell carcinoma (ccRCC) patients after nephrectomy. METHODS: Clinicopathological and survival data from 1289 cT1/2 ccRCC patients treated at the Second Hospital of Tianjin Medical University between 2017 and 2020 were included. Cox regression analysis was used to identify independent risk factors in 902 and 387 ccRCC patients in the training and validation cohorts, respectively, and construct the nomogram. The performance of the nomogram was assessed through calibration plots, time-dependent receiver operating characteristic (ROC) curves, C-index (concordance-index), and decision curve analysis (DCA). Kaplan-Meier curves were used to evaluate the probability of RFS in patients with different recurrence risks. RESULTS: Age, tumor size, surgical approach, Fuhrman grade, and pT3a upstage were identified as independent predictors of RFS. The area under the curve (AUC) for the 3-year and 5-year RFS ROC curves were 0.791 and 0.835 in the training cohort, and 0.860 and 0.880 in the validation cohort. The DCA and calibration plots demonstrated the optimal application and excellent accuracy of the nomogram for predicting 3-year and 5-year RFS. Kaplan-Meier curves revealed significant differences in RFS among the three risk groups in both the training and validation cohorts. Clinically, the developed nomogram provides a more precise tool for risk stratification, enabling tailored postoperative management and surveillance strategies, ultimately aiming to improve patient outcomes. CONCLUSIONS: We developed a nomogram for predicting RFS in cT1/2 ccRCC patients after nephrectomy with high accuracy. The clinical implementation of this nomogram can significantly enhance clinical decision-making, leading to improved patient outcomes and optimized resource utilization in the management of ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Recidiva Local de Neoplasia , Nefrectomia , Nomogramas , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Nefrectomia/métodos , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/diagnóstico , Idoso , Estadiamento de Neoplasias , Estudos Retrospectivos , Curva ROC , Adulto , Fatores de RiscoRESUMO
BACKGROUND: The detection of renal cell carcinoma (RCC) has been rising due to the enhanced utilization of cross-sectional imaging and incidentally discovered lesions with adverse pathology demonstrate potential for metastasis. The purpose of our study was to determine the clinical and multiparametric dynamic contrast-enhanced magnetic resonance imaging (CEMRI) associated independent predictors of adverse pathology for cT1/2 RCC and develop the predictive model. METHODS: We recruited 105 cT1/2 RCC patients between 2018 and 2022, all of whom underwent preoperative CEMRI and had complete clinicopathological data. Adverse pathology was defined as RCC patients with nuclear grade III-IV; pT3a upstage; type II papillary RCC, collecting duct or renal medullary carcinoma, unclassified RCC; sarcomatoid/rhabdoid features. The qualitative and quantitative CEMRI parameters were independently reviewed by two radiologists. Univariate and multivariate binary logistic regression analyses were utilized to determine the independent predictors of adverse pathology for cT1/2 RCC and construct the predictive model. The receiver operating characteristic (ROC) curve, confusion matrix, calibration plot, and decision curve analysis (DCA) were conducted to compare the diagnostic performance of different predictive models. The individual risk scores and linear predicted probabilities were calculated for risk stratification, and the Kaplan-Meier curve and log-rank tests were used for survival analysis. RESULTS: Overall, 45 patients were pathologically confirmed as RCC with adverse pathology. Clinical characteristics, including gender, and CEMRI parameters, including RENAL score, tumor margin irregularity, necrosis, and tumor apparent diffusion coefficient (ADC) value were identified as independent predictors of adverse pathology for cT1/2 RCC. The clinical-CEMRI predictive model yielded an area under the curve (AUC) of the ROC curve of 0.907, which outperformed the clinical model or CEMRI signature model alone. Good calibration, better clinical usefulness, excellent risk stratification ability of adverse pathology and prognosis were also achieved for the clinical-CEMRI predictive model. CONCLUSIONS: The proposed clinical-CEMRI predictive model offers the potential for preoperative prediction of adverse pathology for cT1/2 RCC. With the ability to forecast adverse pathology, the predictive model could significantly benefit patients and clinicians alike by providing enhanced guidance for treatment planning and decision-making.
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Carcinoma de Células Renais , Meios de Contraste , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Masculino , Neoplasias Renais/patologia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Pessoa de Meia-Idade , Meios de Contraste/administração & dosagem , Idoso , Estudos Retrospectivos , Prognóstico , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Seguimentos , Estadiamento de Neoplasias , Curva ROC , Adulto , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Due to the low incidence of nonurothelial bladder cancer (NUBC), there is limited evidence in the field of evidence-based medicine regarding treatment modalities for such diseases. The purpose of our study was to explore the clinicopathological characteristics and prognostic factors of NUBC. METHODS: We retrospectively analyzed the clinical data of 135 bladder squamous cell carcinoma (SqCC) and adenocarcinoma (AC) patients treated at the Second Hospital of Tianjin Medical University between October 2011 and February 2022, including 70 SqCC and 65 AC patients; We also analyzed 145 patients from the Surveillance, Epidemiology, and End Results (SEER) database from 2011 to 2020, including 108 SqCC and 37 AC patients. Clinicopathological characteristics and prognoses were compared between the SqCC and AC groups. Additionally, the KaplanâMeier method and log-rank tests were used to perform survival analysis, and the Cox proportional hazard model was applied to analyze clinical factors affecting prognosis. RESULTS: Comparisons of clinicopathological characteristics between the SqCC and AC groups revealed that age at diagnosis (p < 0.001, p < 0.001), tumor diameter (p < 0.001), tumor location (p = 0.002), and surgical approach (p < 0.001) were significantly different. Univariate and multivariate Cox regression analyses indicated that lymph node metastasis (p = 0.031), advanced pT stage (p < 0.001), and SqCC (p < 0.001) were independent risk factors affecting the prognosis of NUBC patients, and comparisons of clinicopathological characteristics between the SqCC and AC groups from the SEER database revealed that tumor diameter (p < 0.001), tumor location (p = 0.033), tumor number (p = 0.004), surgical approach (p = 0.005), and lymph node metastasis (p = 0.017) were statistically significant. Univariate and multivariate Cox regression analyses indicated that surgical approach (p = 0.003), lymph node metastasis (p = 0.005), age at diagnosis (p = 0.004), and SqCC (p = 0.028) were independent risk factors affecting the prognosis of NUBC patients. CONCLUSIONS: NUBC is a rare pathological subtype of bladder cancer with a poor prognosis, and SqCC and AC are the most common histological subtypes of NUBC. Early diagnosis, radical cystectomy, and a focus on patients with lymph node metastasis, advanced pT stage, or SqCC may be helpful for ensuring the survival of NUBC patients.
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias da Bexiga Urinária , Humanos , Estudos Retrospectivos , Metástase Linfática , Prognóstico , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/diagnóstico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Estadiamento de NeoplasiasRESUMO
Background: Due to the low incidence of nonurothelial bladder cancer (NUBC), there is limited evidence in the field of evidence-based medicine regarding treatment modalities for such diseases. The purpose of our study was to explore the clinicopathological characteristics and prognostic factors of NUBC. Methods: We retrospectively analyzed the clinical data of 135 bladder squamous cell carcinoma (SqCC) and adenocarcinoma (AC) patients treated at the Second Hospital of Tianjin Medical University between October 2011 and February 2022, including 70 SqCC and 65 AC patients; We also analyzed 145 patients from the Surveillance, Epidemiology, and End Results (SEER) database from 2011 to 2020, including 108 SqCC and 37 AC patients. Clinicopathological characteristics and prognoses were compared between the SqCC and AC groups. Additionally, the Kaplan‒Meier method and log-rank tests were used to perform survival analysis, and the Cox proportional hazard model was applied to analyze clinical factors affecting prognosis. Results: Comparisons of clinicopathological characteristics between the SqCC and AC groups revealed that age at diagnosis (p < 0.001, p < 0.001), tumor diameter (p < 0.001), tumor location (p = 0.002), and surgical approach (p < 0.001) were significantly different. Univariate and multivariate Cox regression analyses indicated that lymph node metastasis (p = 0.031), advanced pT stage (p < 0.001), and SqCC (p < 0.001) were independent risk factors affecting the prognosis of NUBC patients, and comparisons of clinicopathological characteristics between the SqCC and AC groups from the SEER database revealed that tumor diameter (p < 0.001), tumor location (p = 0.033), tumor number (p = 0.004), surgical approach (p = 0.005), and lymph node metastasis (p = 0.017) were statistically significant... (AU)
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Humanos , Carcinoma de Células Escamosas , Neoplasias da Bexiga Urinária , Adenocarcinoma , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: We aimed to identify preoperative predictors of aggressive pathology for cT1 solid renal cell carcinoma (RCC) by combining clinical features with qualitative and quantitative CT parameters, and developed a nomogram model. METHODS: We conducted a retrospective study of 776 cT1 solid RCC patients treated with partial nephrectomy (PN) or radical nephrectomy (RN) between 2018 and 2022. All patients underwent four-phase contrast-enhanced CT scans and the CT parameters were obtained by two experienced radiologists using region of interest (ROI). Aggressive pathology was defined as patients with nuclear grade III-IV; upstage to pT3a; type II papillary renal cell carcinoma (pRCC), collecting duct or renal medullary carcinoma, unclassified RCC or sarcomatoid/rhabdoid features. Univariate and multivariate logistic analyses were used to determine significant predictors and develop the nomogram model. To evaluate the accuracy and clinical utility of the nomogram model, we used the receiver operating characteristic (ROC) curve, calibration plot, decision curve analysis (DCA), risk stratification, and subgroup analysis. RESULTS: Of the 776 cT1 solid RCC patients, 250 (32.2%) had aggressive pathological features. The interclass correlation coefficient (ICC) of CT parameters accessed by two reviewers ranged from 0.758 to 0.982. Logistic regression analyses showed that neutrophil-to-lymphocyte ratio (NLR), distance to the collecting system, CT necrosis, tumor margin irregularity, peritumoral neovascularity, and RER-NP were independent predictive factors associated with aggressive pathology. We built the nomogram model using these significant variables, which had an area under the curve (AUC) of 0.854 in the ROC curve. CONCLUSIONS: Our research demonstrated that preoperative four-phase contrast-enhanced CT was critical for predicting aggressive pathology in cT1 solid RCC, and the constructed nomogram was useful in guiding patient treatment and postoperative follow-up.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Nomogramas , Estudos Retrospectivos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: To explore the critical role of the tumor margin irregularity degree (TMID) of renal tumors in predicting adverse pathology of patients with clinical T1/2 (cT1/2) renal cell carcinoma (RCC). METHODS: A total of 821 patients with cT1/2 RCC undergoing nephrectomy in the Second Hospital of Tianjin Medical University between January 2017 and December 2020 were reviewed. The tumor margin irregularity (TMI) was classified into renal mass with locally raised protrusion and smooth margin called 'lobular', sharply and unsmooth nodular margin called 'spiculation', blurred margins between tumor and renal parenchyma or a completely irregular and non-elliptical shape. The ratio between the number of irregular cross-sections (X) and the number of total cross-sections from top to bottom occupied (Y) was defined as TMID (X/Y). The logistic regression was performed to determine the independent predictors of adverse pathology, and the Kaplan-Meier curve and log-rank test were used to analyze the survival outcomes. RESULTS: Among 821 cT1/2 RCC patients, 245 (29.8%) had adverse pathology. The results of the univariate and multivariate logistic regressions showed that the age, tumor size, hemoglobin, and TMID were the independent predictors of adverse pathology. Incorporation of TMID could increase the discrimination of the predictive model with the area under curve (AUC) of ROC curves increasing from 0.725 to 0.808. Patients with adverse pathology or higher TMID both had significantly shorter recurrence-free survival (RFS). CONCLUSION: The nomogram model incorporated with TMID for predicting adverse pathology could increase its discrimination, calibration, and clinical application values, compared with the models without TMID.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Rim , Área Sob a Curva , HospitaisRESUMO
Prostate development and regeneration depend on prostate stem cell function, the delicate balance of stem cell self-renewal and differentiation. However, mechanisms modulating prostate stem cell function remain poorly identified. Here, we explored the roles of Yes-associated protein 1 (YAP) in prostate stem cells, prostate development and regeneration. Using YAPfl/fl, CD133-CreER mice, we found that stem cell-specific YAP-deficient mice had compromised branching morphogenesis and epithelial differentiation, resulting in damaged prostate development. YAP inhibition also significantly affected the regeneration process of mice prostate, leading to impaired regenerated prostate. Furthermore, YAP ablation in prostate stem cells significantly reduced its self-renewal activity in vitro, and attenuated prostate regeneration of prostate grafts in vivo. Further analysis revealed a decrease in Notch and Hedgehog pathways expression in YAP inhibition cells, and treatment with exogenous Shh partially restored the self-renewal ability of prostate sphere cells. Taken together, our results revealed the roles of YAP in prostate stem cell function and prostate development and regeneration through regulation of the Notch and Hedgehog signaling pathways.
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As the most common modification of RNA, N6-methyladenosin (m6A) has been confirmed to be involved in the occurrence and development of various cancers. However, the relationship between m6A and castration resistance prostate cancer (CRPC), has not been fully studied. By m6A-sequencing of patient cancer tissues, we identified that the overall level of m6A in CRPC was up-regulated than castration sensitive prostate cancer (CSPC). Based on the analysis of m6A-sequencing data, we found m6A modification level of HRas proto-oncogene, GTPase (HRAS) and mitogen-activated protein kinase kinase 2 (MEK2 or MAP2K2) were enhanced in CRPC. Specifically, tissue microarray analysis and molecular biology experiments confirmed that METTL3, an m6A "writer" up-regulated after castration, activated the ERK pathway to contribute to malignant phenotype including ADT resistance, cell proliferation and invasion. We revealed that METTL3-mediated ERK phosphorylation by stabilizing the transcription of HRAS and positively regulating the translation of MEK2. In the Enzalutamide-resistant (Enz-R) C4-2 and LNCap cell line (C4-2R, LNCapR) established in the current study, the ERK pathway was confirmed to be regulated by METTL3. We also found that applying antisense oligonucleotides (ASOs) to target the METTL3/ERK axis can restore Enzalutamide resistance in vitro and in vivo. In conclusion, METTL3 activated the ERK pathway and induced the resistance to Enzalutamide by regulating the m6A level of critical gene transcription in the ERK pathway.
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Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia , Androgênios , Receptores Androgênicos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Nitrilas , Proliferação de Células , MetiltransferasesRESUMO
PURPOSE: The study is intended to identify the independent predictors of clinical T1 (cT1) renal cell carcinoma upstaging to pathological T3a (pT3a) and construct the predictive nomogram model. METHODS: The data of cT1 renal cell carcinoma was collected from patients who were treated in the Second Hospital of Tianjin Medical University from January 2010 to December 2016. Mann-Whitney U and chi-square tests were performed to analyze continuous and categorical variables respectively. Univariate and multivariate logistic regression were used to identify the predictors of upstaging. Kaplan-Meier method, log-rank test and Cox regression were performed to analyze survival materials. RESULTS: Among 1,376 cT1 renal cell carcinoma patients, 75 patients were observed upstaging to pT3a, accounting for 5.5%. There were 6 potential predictors of upstaging, i.e age, clinical symptom, tumor size, Fuhrman grade, tumor necrosis and tumor edge regularity. The 5-year recurrence free survival probabilities of upstaging and non-upstaging patients were 73.3% and 91.1%, respectively and upstaging was an independent predictor of recurrence free survival. Two predictive nomograms were constructed and the C-index of them were 0.842 and 0.806, and the calibration curve and decision curve analysis showed highly clinical accuracy of the nomograms. CONCLUSION: Two nomogram models were built to predict the probability of cT1 renal cell carcinoma upstaging to pT3a with highly accuracy and specificity. Upstaging was an independent risk factor of recurrence free survival for cT1 renal cell carcinoma patients.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Nefrectomia/métodos , Fatores de Risco , PrognósticoRESUMO
Background: mRNA vaccines are a novel technology that provide a potential strategy for cancer treatment. However, few studies exist that are focused on the application and development of mRNA vaccines in bladder cancer (BLCA). Therefore, this study filtered candidate antigens and specific mRNA-suitable populations in BLCA via comprehensive multi-omics analysis. Methods: Clinical information, follow-up information, and gene expression profiles were obtained from the TCGA and GEO databases. Somatic mutation and DNA copy number variation of BLCA were visualized by cBioPortal. Significant survival genes were analyzed by GEPIA2. TIMER was used to evaluate the connection between candidate antigens and infiltration of antigen-presenting cells. Consensus clustering analysis was performed to identify immune subtypes using the ConsensusClusterPlus package. The Monocle package was used to visualize the immune landscapes of each BLCA patient. Weighted gene co-expression network analysis (WGCNA) was used to identify key genes for mRNA vaccines. Results: AP2S1, P3H4, and RAC3 were identified as candidate tumor-specific antigens for BLCA. Three immune subtypes were classified based on immune-related gene expression profiles. Patients with the BCS2 subtype were characterized as immune "cold" and exhibited upregulation of immunogenic cell death modulators, whereas patients with BCS1 and BCS3 were immune "hot" and had upregulation of immune checkpoints. Interestingly, patients with the BCS2 subtype had a better prognosis than other subtypes. The immune landscapes of each patient were visualized and revealed the heterogeneity within the BCS1 subtype. Finally, 13 key immune genes were identified. Conclusions: AP2S1, P3H4, and RAC3 were identified as candidate tumor-specific antigens, and patients with the BCS2 and BCS1A subtypes were identified as candidate populations for mRNA vaccines. In summary, this study provides novel insights and a theoretical basis for mRNA vaccine development in BLCA and other malignancies.
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METHODS: Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. RESULTS: AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 µM vs. lenvatinib 1 µM + alisertib 0.1 µM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). CONCLUSIONS: Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.
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Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Dano ao DNA , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Quinolinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Aurora Quinase A/metabolismo , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
BACKGROUND: To evaluate the clinicopathologic value of morphological growth patterns of small renal cell carcinoma (sRCC) and determine the actual demand for taking a rim of healthy parenchyma to avoid positive SM. METHODS: Data was collected from 560 sRCC patients who underwent laparoscopic surgeries from May 2010 to October 2017. One hundred forty-nine cases received nephron-sparing surgery (NSS) and others received radical nephrectomy (RN). All specimens were analyzed separately by two uropathologists, and three morphological growth patterns were identified. The presence of pseudocapsule (PC), surgical margins (SM), and other routine variables were recorded. The relationship between growth patterns and included variables was measured by the χ2 test and Fisher's exact probability test. Survival outcomes were evaluated by Kaplan-Meier method and the log-rank test. RESULTS: The median age of patients was 63.2 years old and the mean tumor diameter was 3.0 cm. Four hundred eighty (85.7%) cases were clear cell RCC and 541 (96.6%) cases were at the pT1a stage. Peritumoral PC was detected in 512 (92.5%) specimens, and the ratio of tumor invasion in PC in infiltration pattern increased obviously than that of the other growth patterns. Similarly, the pT stage was significantly correlated with the infiltration pattern as well. One hundred forty-nine patients underwent NSS and 3 (2.0%) of them showed positive SM after operation. Statistical differences of the 5-year overall survival (OS) and the cancer-specific survival (CSS) existed between different morphological growth patterns, PC status, and pT stages. CONCLUSIONS: Morphological growth patterns of sRCC might be used as a potential biomarker to help operate NSS to avoid the risk of positive SM. How to distinguish different morphological growth patterns before operation and the effectiveness of the growth pattern as a novel proposed parameter to direct NSS in sRCC patients deserves further exploration.
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Neoplasias Renais , Neoplasias Pulmonares , Humanos , Neoplasias Renais/cirurgia , Margens de Excisão , Pessoa de Meia-Idade , Nefrectomia , Néfrons/cirurgia , PrognósticoRESUMO
Background: N6-methyladenosine (m6A)-modified long noncoding RNAs (m6A-lncRNAs) have been proven to be involving in regulating tumorigenesis, invasion, and metastasis for a variety of tumors. The present study aimed to screen lncRNAs with m6A modification and investigate their biological signatures and prognostic values in kidney renal clear cell carcinoma (KIRC). Materials and Methods: lncRNA-seq, miRNA-seq, and mRNA-seq profiles of KIRC samples and the clinical characteristics of corresponding patients were downloaded from The Cancer Genome Atlas (TCGA). The R package "edgeR" was utilized to perform differentially expressed analysis on these profiles to gain DElncRNAs, DEmiRNAs, and DEmRNAs, respectively. The results of intersection of DElncRNAs and m6A-modified genes were analyzed by the weighted gene co-expression network analysis (WGCNA) to screen hub m6A-lncRNAs. Then, WGCNA was also used to construct an lncRNA-miRNA-mRNA (ceRNA) network. The Cox regression analysis was conducted on hub m6A-lncRNAs to construct the m6A-lncRNAs prognostic index (m6AlRsPI). Receiver operating characteristic (ROC) curve was used to assess the predictive ability of m6AlRsPI. The m6AlRsPI model was tested by internal and external cohorts. The molecular signatures and prognosis for hub m6A-lncRNAs and m6AlRsPI were analyzed. The expression level of hub m6A-lncRNAs in KIRC cell lines were quantified by qRT-PCR. Results: A total of 21 hub m6A-lncRNAs associated with tumor metastasis were identified in the light of WGCNA. The ceRNA network for 21 hub m6A-lncRNAs was developed. The Cox regression analysis was performed on the 21 hub m6A-lncRNAs, screening two m6A-lncRNAs regarded as independent prognostic risk factors. The m6AlRsPI was established based on the two m6A-lncRNAs as follows: (0.0006066 × expression level of LINC01820) + (0.0020769 × expression level of LINC02257). The cutoff of m6AlRsPI was 0.96. KM survival analysis for m6AlRsPI showed that the high m6AlRsPI group could contribute to higher mortality. The area under ROC curve for m6AlRsPI for predicting 3- and 5-year survival was 0.760 and 0.677, respectively, and the m6AlRsPI was also tested. The mutation and epithelial-mesenchymal transition (EMT) analysis for m6AlRsPI showed that the high m6AIRsPI group had more samples with gene mutation and had more likely caused EMT. Finally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for mRNAs interacted with the two m6A-lncRNAs, showing they were involved in the process of RNA splicing and regulation of the mRNA surveillance pathway. qRT-PCR analysis showed that the two m6A-lncRNAs were upregulated in KIRC. Conclusion: In the present study, hub m6A-lncRNAs were determined associated with metastasis in KIRC, and the ceRNA network demonstrated the potential carcinogenic regulatory pathway. Two m6A-lncRNAs associated with the overall survival were screened and m6AlRsPI was constructed and validated. Finally, the molecular signatures for m6AlRsPI and the two m6A-lncRNAs were analyzed to investigate the potential modulated processes in KIRC.